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Critical Care

a report by

T i f f a n y M O s bo r n , MD

Former Chair, Section of Critical Care Medicine,Amer ican College of Emergency Physicians

As with other critical disease entities, emergency

medicine plays a key role in the chain of survival for

severe sepsis. An estimated 750,000 patients develop

severe sepsis each year in the US,1 with half initially

presenting to the emergency department (ED).2 A similar

increased incidence has been noted in other countries

across the globe posing a significant healthcare challenge

not only in the US, but worldwide.3,4

In light of this increasing prevalence, the Surviving Sepsis

Campaign (SSC) was formed under the administration of

the Society of Critical Care Medicine, the European

Society of Intensive Care Medicine,and the International

Sepsis Forum.The purpose of the group is to achieve a

mortality reduction of 25% in five years and secure

funding for research and improvements in patient care.5

The treatment for sepsis has evolved and transitioned

from a disease that was primarily treated by critical care

physicians in later phases to one that can be impacted

upon dramatically in early phases by astute and

proactive emergency medicine physicians. Clinical trial

data has suggested that early goal-directed therapy

(EGDT), a definitive resuscitation strategy involving

optimizing systemic oxygen delivery to meet oxygen

demand, is associated with significantly improved

outcomes in sepsis.6

Sepsis syndrome is a disease spectrum that ranges

from an inflammatory response, to sepsis, severe

sepsis, and septic shock. Sepsis is defined as an

inflammatory response with a presumed or identified

source of infection. Severe sepsis is defined as sepsis

with one or more organ system dysfunction. Septic

shock is defined as hypotension (mean arterialpressure (MAP) <65mmHg or systolic blood pressure

(SBP) <90mmHg) after 20–40cc/kg of crystalloid or

colloid equivalent.7

I d en t i f y i n g C an d i d a t e s f o r EGDT

Any patient, identified in within the first six hours of

presenting symptoms, who has a presumed or identified

source of infection and hypotension after a 20–40cc/kg

fluid bolus or a presenting lactate ≥4mmol/L is a

candidate for EGDT. However, many cases are not so

obvious, as initial presentation of septic shock may be

different than later presentation of the disease process.

The use of lactate as a biomarker for tissue oxygenation

and perfusion has enhanced the early identification of

patients with severe sepsis. Early identification allows for

rapid treatment initiation with significant mortality

benefit. Lactate ≥4mmol/L, independent of blood

pressure,was used as a major entry criteria for the EGDT

study which demonstrated a 16% mortality benefit.6

T r e atmen t I n t e r v en t i o n s o f EGDT

The SSC and the Institute for Healthcare Improvement

have introduced a new concept called “treatment

bundles” for the management of severe sepsis and septic

shock. A treatment bundle is a group of interventions

that, when administered together create a synergistic

effect generating improved outcomes which exceed any

one component individually.8 The two bundles that

were developed were the six-hour resuscitation bundle

and a 24-hour subacute care bundle. The six-hour

bundle is comprised of three components, early

identification, early antibiotics and cultures, and early

goal-directed therapy. Once any phase of sepsis

syndrome is identified, antibiotics should be initiated as

soon as possible. If the patient has severe sepsis or septic

shock, the SSC recommends starting antibiotics within

three hours of presentation. Provided that antibiotic

treatment will not be delayed, cultures should be

obtained before antibiotics when possible.

Once the patient has been identified, and antibiotics

and cultures have been initiated, then specific measuresof EGDT should be undertaken. EGDT may be

initiated when hypotension is not resolved after

20–40cc/kg IVF administration, or in patients with a

serum lactate elevation (≥4mmol/L) regardless of blood

pressure. EGDT is a three-stage process aimed at

optimizing oxygen delivery.

The first stage is estmating the extent of hypovolemia

and initiating fluid resuscitation. In severe sepsis and

septic shock a 6–10 liter intravascular fluid deficit is

Ear ly Goal -di rected Therapy in the Treatment of

Severe Seps i s and Sept i c Shock

E M E R G E N C Y M E D I C I N E & C R I T I C A L C A R E R E V I E W 2 0 0 6 23



not uncommon.9 The most efficient method to

determine initial fluid requirements is by monitoring

central venous pressure (CVP) trends. Currently, the

most practical and available means for monitoring

remains an internal jugular, subclavian or femoral

central line.Although non-invasive means of assessing

CVP such as ultrasound evaluation of the internal

jugular vein have shown promise, a triple lumencatheter is preferable in most EDs as it allows for

continuous CVP monitoring while fluids or

medications run uninterrupted in the additional ports.

CVP measurements are not difficult and can be done

by nursing after minimal training. Fluid resuscitation

of a 500cc bolus of crystalloid or colloid equivalent

should be administered every 30 minutes until a CVP

of 8–12mmHg is achieved. If the patient is intubated

resuscitation to a CVP of 12–15 is recommended.The

rate should be modified based upon patient dynamics.

With appropriate volume resuscitation, the cardiac

index may improve by 25–40%10 and up to half of

patients presenting with hypotension may obtain

resolution from fluid replacement alone.11 Although

accurate CVP measurements can be determined from

femoral, internal jugular (IJ) or subclavian (SC) line

placement, central venous oxygen saturation (ScvO2)

measurements require placement of a superior vena

cava, either internal jugular or subclavian, central line.

This value will be critically important in optimizing

therapy later on in the EGDT protocol if initial fluid

boluses are not sufficient.Thus, a subclavian or internal

jugular line is preferable when possible.

If the patient remains hypotensive after fluid boluses, the

second step is to administer vasopressors to optimize the

blood pressure to ≥65mmHg. The MAP may be

transduced off a standard arterial line in either a femoral

or radial location. An arterial line is recommended in

hypotensive patients, especially if vasopressors are

required, as non-invasive BP monitoring in hypotensive

or tachycardic patients may be less accurate.9,12-14 If non-

invasive BP monitoring is the only assessment tool

available, the MAP may be estimated using the equation

MAP = (2DBP+SBP)/3, although this equation has

been shown to be less accurate at higher heart rates. 9 In

some clinical situations, the physician may choose to addvasopressors after the first fluid bolus and titrate down,

keeping the MAP ≥65mmHg, while administering fluid

until CVP goal is attained.

As underscored in two recent opinion papers, much

debate remains regarding the selection of a first line

vasopressor.15,16 One article expressed support for

dopamine rather than norepinephrine as the first-line

vasopressor in sepsis,15 and this remains the vasopressor of

choice in Europe. The other expressed exactly the

opposite opinion,16 supporting norepinephrine, the most

utilized vasopressor in the US for septic shock. The

primary difference between the two vasopressors is the

degree to which the different agents affect cardiac index

and systemic vascular resistance to increase MAP.

Dopamine promotes MAP primarily through increased

cardiac index, with little effect on SVR, while

norepinephrine increases MAP primarily throughincreased SVR, with a lesser effect on cardiac index.

Dopamine should be avoided in tachycardic patients

(HR>120bpm). Although the SSC has stated that no

definitive data supports the preference of either dopamine

or norepinephrine and either may be considered as a first-

line agent, they indicate vasopressin should be used with

caution as an adjunct until further data are available.

The third phase is evaluating the ScvO2 to assess adequate

tissue oxygenation. ScvO2 is the oxygen saturation of

venous blood in the superior vena cava as it enters the

right atria and provides a direct measurement of tissue

hypoxia.Adequate tissue oxygenation cannot be assumed

until biomarkers reflective of tissue perfusion have been

normalized.Arterial oxygen saturation measured as blood

is ejected from the heart is about 100%.As the oxygenated

blood circulates through the microvasculature, the

peripheral tissues extract an estimated 25% of delivered

oxygen. This is normally measured by evaluating the

oxygen saturation in the pulmonary artery (SVO2)

through a pulmonary artery catheter.However,a practical

alternative is to measure the ScvO2 through a central line,

at the level of the right atria.This is measured by doing a

venous blood gas sampled from the distil (brown) port of

a typical IJ or SC central line, and specifically looking at

oxygen saturation.The goal is a ScvO2 ≥70%.ScvO2 can

be measured by individual blood draws from a typical

super vena cava central line or by using a central line that

allows for continuous monitoring. The benefit of

continuous monitoring is immediate ability to assess the

effect of treatment interventions on oxygen delivery at

the bedside. It provides dynamic, immediate feedback

which enables the emergency physicians to adjust

treatment to realtime physiologic data without

pulmonary artery catheterization or other highly invasive

intensive care unit (ICU)-based techniques that are

impractical in an ED environment. A catheter which

allows for continuous ScvO2 monitoring is inserted in thesame manner as a traditional triple lumen catheter at a

subclavian or internal jugular site. The catheter has an

infared right which allows for oxygen saturation

measurement and an extra port which is attached to a

monitor that displays the ScvO2 after calibration. If the

EP does not have access to this equipment, the ScvO2

may be estimated off of serial venous blood gas analysis

whenever major therapeutic interventions have been

done.This approach,however,is more labor-intensive and

does not provide realtime physiologic monitoring,

Critical Care

24 E M E R G E N C Y M E D I C I N E & C R I T I C A L C A R E R E V I E W 2 0 0 6



DR40197 0406 PRINTED IN USA. © 2006, ELI LILLY AND COMPANY. ALL RIGHTS RESERVED. Xigris is a registered trademark of Eli Lilly and Company.

Xigris is indicated for the reduction of mortality in adult patients withsevere sepsis (sepsis associated with acute organ dysfunction) who havea high risk of death (e.g., as determined by APACHE II†).

Xigris is not indicated in adult patients with severe sepsis and lower risk of death. Safety and efficacy have not been established in pediatric

patients with severe sepsis.Bleeding is the most common adverse reaction associated with Xigristherapy. In the Phase 3 study, serious bleeding events were observedduring the 28-day study period in 3.5% of Xigris-treated and 2.0%of placebo-treated patients. The difference in serious bleedingoccurred primarily during infusion. Intracranial hemorrhage wasalso reported. The risk of ICH may be increased in patients with risk fac-tors for bleeding such as severe coagulopathy and severe thrombocy-topenia. Should clinically important bleeding occur, immediately stop theXigris infusion.

Xigris is contraindicated in patients in clinical situations in which bleed-ing could be associated with a high risk of death or significant morbid-ity. Certain conditions are likely to increase the risk of bleeding withXigris therapy. Additionally, in a subset of patients with single organ dys-function and recent surgery from two separate placebo-controlled trials,all-cause mortality was numerically higher in the Xigris groups com-

pared to the placebo group. Patients with single organ dysfunction andrecent surgery may not be at high risk of death irrespective of APACHEII score, and therefore not among the indicated population.

Please see Brief Summary on adjacent page for Contraindications, Warnings, and other Impor tant Safety Information, or visit www.Xigris.com

† APACHE (Acute Physiology And Chronic Health Evaluation). For more information onusing the APACHE II scoring system, please see http://www.sfar.org/scores2/scores2.html

* As defined by an increase in inflammation and coagulation and a decrease in fibrinolysis.The specific mechanisms by which Xigris exerts its effect on survival in patients with severesepsis are not completely understood.

While supportive care treats the symptomsof severe sepsis, Xigris reduces microvascular

dysfunction,an underlying cause.*

Improve survival in your high-risk patients.Treat beneath the symptoms.

S O M O R E S U R V I V E

R e s p o n d w i t h X i g r i s.

L o o k b e n e a t h t h e s y m p t o m s .



XIGRISDrotrecogin alfa (activated)BRIEF SUMMARY: Consult the Xigris package insert for complete prescribing information.

CLINICAL STUDIES: The efficacy of Xigris was studied in an international, randomized,double blind, placebo-controlled trial (PROWESS) of 1690 patients with severe sepsis.Patients received a 96-hour infusion of Xigris at 24 mcg/kg/hr or placebo startingwithin 48 hours after the onset of the first sepsis induced organ dysfunction.

The study was terminated after a planned interim analysis due to significantly lowermortality in patients on Xigris than in patients on placebo (210/850, 25% vs 259/840,31% p=0.005).

The observed mortality difference between Xigris and placebo was limited to the halfof patients with higher risk of death, i.e., APACHE II score ≥25, the 3rd and 4th quartileAPACHE II scores. The efficacy of Xigris has not been established in patients withlower risk of death, e.g., APACHE II score <25.

This is a short summary of the CLINICAL STUDIES section from the completeprescribing information.

INDICATIONS AND USAGE: Xigris is indicated for the reduction of mortality in adultpatients with severe sepsis (sepsis associated with acute organ dysfunction) whohave a high risk of death (e.g., as determined by APACHE II, see CLINICAL STUDIESin the full Prescribing Information).

Xigris is not indicated in adult patients with severe sepsis and lower risk of death(see CLINICAL STUDIES in the full Prescribing Information). Safety and efficacy havenot been established in pediatric patients with severe sepsis.

CONTRAINDICATIONS: Xigris increases the risk of bleeding. Xigris is contraindicatedin patients with the following clinical situations in which bleeding could be associatedwith a high risk of death or significant morbidity:

• Active internal bleeding• Recent (within 3 months) hemorrhagic stroke• Recent (within 2 months) intracranial or intraspinal surgery, or severe head trauma• Trauma with an increased risk of life-threatening bleeding• Presence of an epidural catheter• Intracranial neoplasm or mass lesion or evidence of cerebral herniationXigris is contraindicated in patients with known hypersensitivity to drotrecogin alfa

(activated) or any component of this product.

WARNINGS: Bleeding—Bleeding is the most common serious adverse effectassociated with Xigris therapy. Each patient being considered for therapy with Xigrisshould be carefully evaluated and anticipated benefits weighed against potential risksassociated with therapy.

Certain conditions, many of which led to exclusion from the Phase 3 trial, are likelyto increase the risk of bleeding with Xigris therapy. For individuals with one or moreof the following conditions, the increased risk of bleeding should be carefully consideredwhen deciding whether to use Xigris therapy:

• Concurrent therapeutic dosing of heparin to treat an active thrombotic or embolicevent (see PRECAUTIONS, Drug Interactions)

• Platelet count <30,000 x 106 /L, even if the platelet count is increased aftertransfusions

• Prothrombin time-INR >3.0• Recent (within 6 weeks) gastrointestinal bleeding• Recent administration (within 3 days) of thrombolytic therapy• Recent administration (within 7 days) of oral anticoagulants or glycoprotein IIb/IIIa

inhibitors• Recent administration (within 7 days) of aspirin >650 mg per day or other platelet

inhibitors• Recent (within 3 months) ischemic stroke (see CONTRAINDICATIONS)• Intracranial arteriovenous malformation or aneurysm

• Known bleeding diathesis• Chronic severe hepatic disease• Any other condition in which bleeding constitutes a significant hazard or would be

particularly difficult to manage because of its locationShould clinically important bleeding occur, immediately stop the infusion of Xigris.

Continued use of other agents affecting the coagulation system should be carefullyassessed. Once adequate hemostasis has been achieved, continued use of Xigris maybe reconsidered.

Xigris should be discontinued 2 hours prior to undergoing an invasive surgicalprocedure or procedures with an inherent risk of bleeding. Once adequate hemostasishas been achieved, initiation of Xigris may be reconsidered 12 hours after majorinvasive procedures or surgery or restarted immediately after uncomplicated less invasiveprocedures.

Mortality in Patients with Single Organ Dysfunction and Recent Surgery—Amongthe small number of patients enrolled in PROWESS with single organ dysfunction andrecent surgery (surgery within 30 days prior to study treatment) all-cause mortalitywas numerically higher in the Xigris group (28-day: 10/49; in-hospital: 14/48)compared to the placebo group (28-day: 8/49; in-hospital: 8/47).

In an analysis of the subset of patients with single organ dysfunction and recentsurgery from a separate, randomized, placebo-controlled study (ADDRESS) of septicpatients not at high risk of death all-cause mortality was also higher in the Xigris group

(28-day: 67/323; in-hospital: 76/325) compared to the placebo group (28-day:44/313; in-hospital: 62/314). Patients with single organ dysfunction and recentsurgery may not be at high risk of death irrespective of APACHE II score and thereforenot among the indicated population.

PRECAUTIONS: Laboratory Tests—Most patients with severe sepsis have a coagulopathythat is commonly associated with prolongation of the activated partial thromboplastintime (APTT) and the prothrombin time (PT). Xigris may variably prolong the APTT.Therefore, the APTT cannot be reliably used to assess the status of the coagulopathyduring Xigris infusion. Xigris has minimal effect on the PT and the PT can be used tomonitor the status of the coagulopathy in these patients.

Immunogenicity—As with all therapeutic proteins, there is a potential for immuno-genicity. The incidence of antibody development in patients receiving Xigris has notbeen adequately determined, as the assay sensitivity is inadequate to reliably detect allpotential antibody responses. One patient in the Phase 2 trial developed antibodiesto Xigris without clinical sequelae. One patient in the Phase 3 trial who developedantibodies to Xigris developed superficial and deep vein thrombi during the study, anddied of multi-organ failure on day 36 post-treatment but the relationship of this eventto antibody is not clear.

Xigris has not been readministered to patients with severe sepsis.Drug Interactions—Drug interaction studies with Xigris have not been performed in

patients with severe sepsis. However, since there is an increased risk of bleeding withXigris, caution should be employed when Xigris is used with other drugs that affecthemostasis (see CLINICAL PHARMACOLOGY, WARNINGS in the full PrescribingInformation). Approximately 2/3 of the patients in the Phase 3 study received eitherprophylactic low dose heparin (unfractionated heparin up to 15,000 units/day) orprophylactic doses of low molecular weight heparins as indicated in the prescribinginformation for the specific products. Concomitant use of prophylactic low doseheparin did not appear to affect safety, however, its effects on the efficacy of Xigrishave not been evaluated in an adequate and well-controlled clinical trial.

Drug/Laboratory Test Interaction—Because Xigris may affect the APTT assay,Xigris present in plasma samples may interfere with one-stage coagulation assaysbased on the APTT (such as factor VIII, IX, and XI assays). This interference mayresult in an apparent factor concentration that is lower than the true concentration.Xigris present in plasma samples does not interfere with one-stage factor assaysbased on the PT (such as factor II, V, VII, and X assays).

Carcinogenesis, Mutagenesis, Impairment of Fertility—Long-term studies inanimals to evaluate potential carcinogenicity of Xigris have not been performed.

Xigris was not mutagenic in an in vivo micronucleus study in mice or in an in vitro chromosomal aberration study in human peripheral blood lymphocytes with or withoutrat liver metabolic activation.

The potential of Xigris to impair fertility has not been evaluated in male or femaleanimals.

Pregnancy Category C—Animal reproductive studies have not been conducted withXigris. It is not known whether Xigris can cause fetal harm when administered toa pregnant woman or can affect reproduction capacity. Xigris should be givento pregnant women only if clearly needed.

Nursing Mothers—It is not known whether Xigris is excreted in human milk orabsorbed systemically after ingestion. Because many drugs are excreted in humanmilk, and because of the potential for adverse effects on the nursing infant, a decisionshould be made whether to discontinue nursing or discontinue the drug, taking intoaccount the importance of the drug to the mother.

Pediatric Use—The safety and effectiveness of Xigris have not been established inthe age group newborn (38 weeks gestational age) to 18 years. The efficacy of Xigrisin adult patients with severe sepsis and high risk of death cannot be extrapolated topediatric patients with severe sepsis.

Geriatric Use—In clinical studies evaluating 1821 patients with severe sepsis,approximately 50% of the patients were 65 years or older. No overall differences insafety or effectiveness were observed between these patients and younger patients.

ADVERSE REACTIONS: Bleeding—Bleeding is the most common adverse reactionassociated with Xigris. In the Phase 3 study, serious bleeding events were observedduring the 28-day study period in 3.5% of Xigris-treated and 2.0% of placebo-treatedpatients, respectively. The difference in serious bleeding between Xigris and placebooccurred primarily during the infusion period and is shown in Table 1.1 Seriousbleeding events were defined as any intracranial hemorrhage, any life-threateningbleed, any bleeding event requiring the administration of ≥3 units of packed red bloodcells per day for 2 consecutive days, or any bleeding event assessed as a seriousadverse event.

Table 1: Number of Patients Experiencing a Serious Bleeding Event bySite of Hemorrhage During the Study Drug Infusion Perioda In PROWESS1

Xigris PlaceboN=850 N=840

Total 20 (2.4%) 8 (1.0%)Site of Hemorrhage

Gastrointestinal 5 4Intra-abdominal 2 3Intra-thoracic 4 0Retroperitoneal 3 0Intracranial 2 0Genitourinary 2 0Skin/soft tissue 1 0Otherb 1 1a Study drug infusion period is defined as the date of initiation of study drug to thedate of study drug discontinuation plus the next calendar day.

b Patients requiring the administration of ≥3 units of packed red blood cells per dayfor 2 consecutive days without an identified site of bleeding.

In PROWESS, 2 cases of intracranial hemorrhage (ICH) occurred during the infu-sion period for Xigris-treated patients and no cases were reported inthe placebo patients. The incidence of ICH during the 28-day study period was 0.2%for Xigris-treated patients and 0.1% for placebo-treated patients. ICH has been report-ed in patients receiving Xigris in non-placebo controlled trials with an incidence ofapproximately 1% during the infusion period. The risk of ICH may be increased inpatients with risk factors for bleeding such as severe coagulopathy and severe throm-bocytopenia (see WARNINGS).

In PROWESS, 25% of the Xigris-treated patients and 18% of the placebo-treatedpatients experienced at least one bleeding event during the 28-day study period. Inboth treatment groups, the majority of bleeding events were ecchymoses or gastroin-testinal tract bleeding.

Other Adverse Reactions—Patients administered Xigris as treatment for severesepsis experience many events which are potential sequelae of severe sepsis and mayor may not be attributable to Xigris therapy. In clinical trials, there were no types ofnon-bleeding adverse events suggesting a causal association with Xigris.

REFERENCES:1. Bernard GR, et al. Efficacy and Safety of Recombinant Human Activated Protein C

for Severe Sepsis. N Engl J Med. 2001;344:699-709.

Literature revised June 23, 2005

PV 3427 AMP PRINTED IN USA

Eli Lilly and CompanyIndianapolis, IN 46285, USA

www.lilly.com

Copyright © 2001, 2005, Eli Lilly and Company. All rights reserved.

XIGRIS (drotrecogin alfa [activated]) PV 3427 AMP XIGRIS (drotrecogin alfa [activated]) PV 3427 AMP



relatively delaying analysis of therapeutic interventions.

If, despite adequate CVP and MAP, the ScvO2

remains below 70%, a post-resuscitation hematocrit

(Hct) should be evaluated.A post-resuscitation HCT

is used due to potential pseudo-elevation from initial

hypovolemia induced hemoconcentration. If the Hct

<30%, the patient should be transfused to a Hct≥30% to facilitate oxygen delivery through optimized

hemoglobin concentration.

If goal CVP, MAP and HCT are achieved and the

ScvO2 remains <70%, consider an inotropic agent to

enhance cardiac output and tissue oxygenation. Once

preload, afterload and the concentration of oxygen

carrying units are optimized, the remaining component

of oxygen delivery to be addressed is cardiac output.

Although sepsis is commonly characterized as

hyperdynamic, some patients may present in the early

stages with a decreased preload and myocardial

depression reflecting a hypodynamic state (i.e. low

cardiac output).17 Myocardial depression, thought to

occur as a result of effects of inflammatory mediators,

can be the predominant hemodynamic feature in

15–20% of patients presenting with severe sepsis/septic

shock and may be especially profound in patients with

pre-existing cardiac disease.18 Dobutamine is the most

readily available and most commonly used inotropic

agent, and may be used in patients with a MAP ≥65 and

a heart rate <120bpm.Once the CVP, MAP, and ScvO2

goals have been reached, the EGDT component of the

resuscitation has been completed.

Ot h e r A d j u n c t s

Beyond the EGDT protocol, other therapeutic options

from the 24-hour bundle may be considered such as the

administration of steroids, vasopressin, activated protein

C (drotrecogin alpha or Xigris) and lung protective

strategies for mechanically ventilated patients.

S t e r o i d A d m i n i s t r a t i o n

As 50–70% of patients in vasopressor dependent shock

may have adrenal insufficiency, corticosteroid

administration should be considered. In one study,administration of corticosteroids to vasopressor

dependent septic shock patients who failed an

adrenocorticotropic hormone (ACTH) stimulation test

resulted in a 28-day mortality benefit of 10% (63%

placebo vs 53% treatment CI, 0.66–1.04; p=0.04).

Additionally, time on vasopressors was significantly

reduced when inadequate adrenal reserve was treated.The

benefits were achieved without increases in infectious

complications, gastrointestinal bleeding, or mental status

changes. However, there was no improvement in survival

when patients with an appropriate cortisol response to

ACTH were treated with steroids.19

V a s op r e s s i n

Vasopressin is an endogenous stress hormone released

during vasodilatory shock. In the patient with

refractory hypotension, vasopressin deficiency shouldbe considered. When administered in relatively small,

physiologic doses, vasopressin administration

(0.01–0.04 units/min), corrects the deficiency through

a hypersensitive and synergistic physiologic response

that increases MAP and frequently allows for

catecholamine withdrawal.20,21 However, vasopressin is

not considered a first-line agent, and should be used in

combination with other vasoactive drugs. Dosages

greater than 0.04U/min are not of greater benefit and

may be harmful.10

A c t i v a t e d P ro t e i n C

Activated protein C (drotrecoogin alpha, Xigris) has

potent anticoagulant, pro-fibrinolytic, anti-

inflammatory, and anti-apoptotic effects. Drotrecoogin

alpha works to reverse a septic cascade of microvascular

thrombi that cause capillary flow occlusion. Survival

benefit with drotrecogin alfa (activated) is associated

with higher severity of illness, described by either the

number of sepsis-induced organ failures (≥2) or the

Acute Physiology and Chronic Health Evaluation II

(APACHE II) score (>25).Although early studies show

promise, there are significant risks with the most

prevalent being bleeding.22

Low T id a l Vo lu m e V e n t i l a t i on

The SSC endorsed low tidal volume ventilation

(6cc/kg) and minimal plateau pressure for patients

with acute lung injury or at risk for acute respiratory

distress syndrome (ARDS).Although not specifically a

therapy for severe sepsis/septic shock, a large

multicenter trial from the ARDS Network showed

that the use of low-tidal volume mechanical

ventilation,when acute lung injury is present, reduced

mortality rates from 39.8% to 31%.10,23

G l u c o s e C o n t r o l

Tight glucose control with blood sugars aggressively

held <110mg/dl during the length of the ICU stay has

been demonstrated to reduce mortality. While tight

glucose control may be less important in the acute

phases of resuscitation, it has been hypothesized that

hyperglycemia exacerbates the inflammatory cascade,

and thus should be considered in the early phases of

treatment when possible.

Ear l y Goal -d i rec ted Therapy in the Treatment of Severe Seps i s and Sept i c Shock

E M E R G E N C Y M E D I C I N E & C R I T I C A L C A R E R E V I E W 2 0 0 6 27



E M E R G E N C Y M E D I C I N E & C R I T I C A L C A R E R E V I E W 2 0 0 628

Critical Care

Prophy lax i s

Typical prophylactic measures should be undertaken,

including stress ulcer prophylaxis and deep vein thrombosis

(DVT) prophylaxis. Underlying coagulopathies and other

complicating factors may prevent DVT prophylaxis from

beginning in the ED; however stress ulcer prophylaxis with

a H2 blocker can be administered routinely.

Con c l u s i o n

Early goal directed therapy produces a reduction

in hospital mortality.The algorithm for the management

of severe sepsis and septic shock revolves around early

diagnosis, early antibiotics, EGDT and adjunctive

therapies in the persistently hypotensive patient, and

generally begins in the ED. ■

Re f e r en c e s

1. Angus, D C, Linde-Zwirble W T, et al.,“Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and

associated costs of care” Crit Care Med (2001);29(7): pp. 1,303–1,310.

2. Rivers E P, Nguyen H B, Huang D T, Donnino M W, “Critical Care and Emergency Medicine”, Curr Opin Crit Care

(2002);8(6): pp. 600–606.

3. Brun-Buisson C, Meshaka P, Pinton P, et al., and the EPISEPSIS Study Group,“EPISEPSIS: a reappraisal of epidemiology

and outcome of severe sepsis in French intenswive care units”, Intensive Care Med (2004);30: pp. 580–588.

4. Finfer S, Bellomo R, Lipman J, et al.,“Adult Population incidence of severe spepsis in Australian and New Zealand intensive

care units”, Intensive Care Med (2004);30: pp. 536–555.

5. Osborn T M, Nguyen H B, Rivers E P,“Emergency medicine and the surviving sepsis campaign: an international approach to

managing severe sepsis and septic shock”, Ann of Emerg Med (2005);46(3): pp. 228–231.

6. Rivers E, Nguyen B, Havstad S, et al.,“Early goal-directed therapy in the treatment of severe sepsis and septic shock”, N Engl

J Med (2001);345(19): pp. 1,368–1,377.

7. Levy M M, Fink M P, et al., “2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference”,

Intensive Care Med (2003);29 (4): pp. 530–538.

8. Resar R,“Sepsis Bundle History”,Available at http://www.ihi.org

9. Hollenberg S M,Ahrens T S, et al.,“Practice parameters for hemodynamic support of sepsis in adult patients: 2004 update”,Crit

Care Med (2004);32(9): pp. 1,928–1,948.

10. Packman M I,Rackow E C,“Optimum left heart filling pressure during fluid resuscitation of patients with hypovolemic and septic

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